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Series GSE54979 Query DataSets for GSE54979
Status Public on Jan 20, 2015
Title Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy
Organism Homo sapiens
Experiment type Expression profiling by array
Summary ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration.
 
Overall design Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.
 
Contributor(s) Zhang R
Citation(s) 25686104
Submission date Feb 13, 2014
Last update date Aug 13, 2018
Contact name Louise C Showe
E-mail(s) lshowe@wistar.org
Phone 215-898-3791
Organization name The Wistar Institute
Lab Dr. Louise Showe
Street address 3601 Spruce St
City Philadelphia
State/province PA
ZIP/Postal code 19104
Country USA
 
Platforms (1)
GPL10558 Illumina HumanHT-12 V4.0 expression beadchip
Samples (9)
GSM1327414 DMSO.1
GSM1327415 DMSO.2
GSM1327416 DMSO.3
Relations
BioProject PRJNA238190

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE54979_RAW.tar 26.2 Mb (http)(custom) TAR
GSE54979_non-normalized.txt.gz 2.8 Mb (ftp)(http) TXT
Raw data are available on Series record
Processed data included within Sample table

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